Oligonucleotide-based medicinal products: A review of current regulatory requirements for preclinical studies
Year: 2026
Type: article
Abstract: INTRODUCTION. Oligonucleotides represent a promising class of drugs with unique physicochemical properties, pharmacokinetic characteristics, mechanisms of action, and encouraging therapeutic potential. Due to the lack of a national Russian guideline and a guideline currently effective within the Eurasian Economic Union (EAEU), existing international regulatory requirements for the preclinical safety assessment of oligonucleotides were reviewed. AIM. To analyze regulatory documents and scientific and methodological sources addressing current approaches to the preclinical development of therapeutic oligonucleotides. DISCUSSION. Oligonucleotides represent an established class of medicinal products consisting of chemically synthesized compounds that are polymorphic in structure and mechanism of action, possessing highly specific pharmacological activity. The pharmacological action of oligonucleotides is based on the specific binding of synthetically modified RNA or RNA/DNA hybrids to target RNA sequences to alter RNA expression and/or subsequent protein expression. Oligonucleotides can vary by mechanism of action, structure, chemical modifications, size, sequence, delivery strategy, as well as by the presence or absence of other functional groups, such as small molecules, proteins, or antibodies. In terms of target and species specificity, these drugs occupy an intermediate position between small molecules and biologics. Currently, antisense oligonucleotides, small interfering RNAs, and aptamers are successfully utilized in clinical practice. Local guidelines for the preclinical safety assessment of oligonucleotides proposed by the Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) serve as an interim step prior to the release of the globally harmonized International Council for Harmonisation (ICH) S13 guideline, which is currently being developed by international regulators. In accordance with the Fundamental Scientific Research Program in the Russian Federation for the 2021–2030 period, which states the goal of creating technologies for silencing damaged genes using oligonucleotides, the development of a guideline for the preclinical studies of oligonucleotides is considered appropriate. CONCLUSIONS. Therapeutic oligonucleotides have a dual nature, combining the characteristics of small chemical molecules and highly specific biotechnological products. Since oligonucleotide development is a dynamically evolving scientific field, it is advisable to utilize a flexible, case-by-case approach when planning and conducting preclinical studies. This approach should account for chemical modification, mechanism of action, delivery method, and current scientific knowledge regarding the potential toxic effects of this drug class.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7220660752